The objective is to search for mechanisms by which the female hormones, progesterone and estrogen, influence vaginal transmission and pathogenesis of Simian Immunodeficiency Virus (SIV) in rhesus macaques. Progesterone?s known effects on female physiology are numerous. They include thinning of vaginal epithelium and immune suppression. In a recent study, progesterone was shown to increase SIV vaginal transmission. Thinning the vaginal barrier to SIV infection is a potential cause of this increase, but immune suppression, possible increases in target cells in vaginal tissues or direct effects on in vivo SIV replication need study. Moreover, an important inference from the progesterone study was that estrogen, an antagonist of progesterone, may actually protect against SIV vaginal transmission. Two specific aims are proposed to identify and characterize the action of progesterone, estrogen and the anovulatory state in vaginal transmission and pathogenesis of SIV. Aim 1. To individually test the effects of progesterone and estrogen on SIV vaginal transmission and their effects on SIV pathogenesis and the SIV immune response. Aim 2. To test progesterone and estrogen on in vivo pathogenesis independent of vaginal mucosal changes through intravenous infection of hormone treated- macaques. In both aims, each hormone will be examined independently by testing virus load, clinical outcome and immune responses in ovariectomized macaques with and without progesterone and estrogen implants. Ovariectomy is a standard technique for individual in vivo study of the sex hormones. Natural states of elevated hormones or their absence as in menopause, bear on vaginal physiology and may therefore, influence vaginal transmission of human immunodeficiency virus (HIV). Moreover, drugs based on these hormones are used in female contraceptives. Because human epidemiologic studies are difficult to design and control, an understanding of hormones gained in the SIV model may help to elucidate the effects of these natural and drug-based co-factors on HIV vaginal transmission. FUNDING NIH (1R01 AI41952) PUBLICATIONS Sodora, D.L., A. Gettie, C.J. Miller and P.A. Marx. Vaginal transmission of SIV assessing infectivity and hormonal influences in macaques inoculated with cell-free and cell-associated viral stocks. AIDS Research and Human Retroviruses, 13:S1-S5.